U.S. patent application number 11/648274 was filed with the patent office on 2007-07-05 for n-arylshydroxyalkylidene-carboxamide compositions and methods.
Invention is credited to Edward T. Wei.
Application Number | 20070155755 11/648274 |
Document ID | / |
Family ID | 38941837 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070155755 |
Kind Code |
A1 |
Wei; Edward T. |
July 5, 2007 |
N-arylshydroxyalkylidene-carboxamide compositions and methods
Abstract
N-(Substituted-aryl-hydroxyalkylidene)-cycloalkyl carboxamide
compositions are disclosed that target molecular elements on
sensory nerves. These compounds, preferably administered topically,
inhibit the perception of itch and pain and have prolonged duration
of action.
Inventors: |
Wei; Edward T.; (Berkeley,
CA) |
Correspondence
Address: |
Edward T. Wei
480 Grizzly Peak Blvd.
Berkeley
CA
94708
US
|
Family ID: |
38941837 |
Appl. No.: |
11/648274 |
Filed: |
December 29, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11064358 |
Feb 22, 2005 |
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11648274 |
Dec 29, 2006 |
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60547263 |
Feb 23, 2004 |
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60857897 |
Nov 8, 2006 |
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Current U.S.
Class: |
514/255.01 ;
514/255.06; 514/263.1; 514/266.1; 514/298; 514/310; 514/312;
514/355; 514/365; 514/372; 514/400; 514/411; 514/423; 514/443;
514/616 |
Current CPC
Class: |
A61P 17/00 20180101;
A61K 31/164 20130101; A61P 25/00 20180101; A61P 29/00 20180101;
A61P 11/04 20180101; A61K 31/16 20130101; A61K 31/165 20130101;
A61K 9/006 20130101; A61P 11/00 20180101; A61K 9/2018 20130101;
A61P 17/04 20180101; A61K 9/0014 20130101; A61P 11/14 20180101;
A61K 9/0056 20130101; A61K 9/0073 20130101; A61P 11/02 20180101;
A61K 9/2027 20130101 |
Class at
Publication: |
514/255.01 ;
514/255.06; 514/263.1; 514/266.1; 514/310; 514/312; 514/411;
514/365; 514/372; 514/443; 514/400; 514/423; 514/355; 514/616;
514/298 |
International
Class: |
A61K 31/4965 20060101
A61K031/4965; A61K 31/52 20060101 A61K031/52; A61K 31/517 20060101
A61K031/517; A61K 31/47 20060101 A61K031/47; A61K 31/502 20060101
A61K031/502; A61K 31/498 20060101 A61K031/498; A61K 31/473 20060101
A61K031/473; A61K 31/426 20060101 A61K031/426; A61K 31/425 20060101
A61K031/425 |
Claims
1. A therapeutic composition comprising an amount of a N-acylated
conjugate between 2-isopropyl-5-methyl-cyclohexanecarboxylic acid
and the amino group of a sympathomimetic drug, the conjugate being
biologically active and in an amount effective to treat sensory
discomfort.
2. The composition as in claim 1 wherein the sympathomimetic drug
is an .alpha.-adrenergic receptor agonist.
3. The composition as in claim 1 wherein the N-acylated conjugate
is 2-Isopropyl-5-methyl-cyclohexanecarboxylic acid
[2'-hydroxy-2'-(3''-hydroxy-phenyl)-ethyl]-N-methyl-amide.
4. A composition useful for counteracting sensory irritation, itch
and pain, comprising: a biologically active compound carried by a
delivery vehicle, the compound having the structure of Formula 1,
R--CO--N(R'')--R'--Y Formula 1 where a) R is
(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl, b) R'' is hydrogen,
methyl, ethyl, n-propyl, or isopropyl c) R' is a divalent C.sub.2
to C.sub.4 hydroxyalkylidenyl radical, d) Y is a substituted-aryl,
or -heterocyclyl, where the aryl or heterocyclyl includes phenyl,
1-naphthyl, indenyl, azulenyl, heptalenyl, indacenyl, pyridinyl,
dihydropyridinyl, pyridazinyl, piperazinyl, pyrmidinyl, pyrazinyl,
indolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl,
quinazolinyl, carbazolyl, pyrrolyl, thiazolyl, isothiazolyl,
imidazolyl, benzothiophenyl, and phenathridinyl; and where one to
five of the substituent(s) on the aryl or heterocyclyl being one or
more of halogen, or C.sub.1 to C8 alkyl, or alkenyl, or hydroxyl,
or C.sub.1 to C.sub.8 hydroxyalkyl, or C.sub.1 to C.sub.8 alkoxy,
or C.sub.2 to C.sub.10 alkylcarbonyloxy, or C.sub.2 to C.sub.10
carboxyalkyl or alkylcarboxyalkyl, or C.sub.3 to C.sub.10
alkylcarbonyloxyalkyl, or C.sub.2 to C.sub.8 acyl, or amino,
C.sub.1 to C.sub.8 alkylamino, or C.sub.2 to C.sub.10 acylamino, or
sulfonamido or C.sub.1 to C.sub.8 alkylsufonylamino, or
N-arylsulfonamido or N-heterocyclylsulfonamido and where the aryl
or heterocyclyl is selected from the group phenyl, benzyl, oxazoyl,
thiazoyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, and where the
aryl or heterocyclyl moiety is optionally substituted with a) up to
three C.sub.1 to C.sub.3 alkyl groups, b) up to three C.sub.1 to
C.sub.3 alkoxy groups, c) C.sub.1 to C.sub.8 aminoalkyl or
diaminoalkyl, d) C.sub.2 to C.sub.10 alkylaminoalkyl, e) C.sub.2 to
C.sub.10 acylaminoalkyl, f) carboxy, or g) C.sub.2 to C.sub.10
alkylcarboxy; the delivery vehicle adapted for topical
delivery.
5. The composition as in claim 4 wherein the biologically active
compound is in an amount of from about 0.1 wt. % to about 2 wt. %
of the delivery vehicle.
6. A method for treating sensory discomfort, comprising:
administering a composition having a biologically active compound
carried by a delivery vehicle, the compound having the structure of
Formula 1, R--CO--N(R'')--R'--Y Formula 1 where e) R is
(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl, f) R'' is hydrogen,
methyl, ethyl, n-propyl, or isopropyl g) R' is a divalent C.sub.2
to C.sub.4 hydroxyalkylidenyl radical, h) Y is a substituted-aryl,
or -heterocyclyl, where the aryl or heterocyclyl includes phenyl,
1-naphthyl, indenyl, azulenyl, heptalenyl, indacenyl, pyridinyl,
dihydropyridinyl, pyridazinyl, piperazinyl, pyrmidinyl, pyrazinyl,
indolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl,
quinazolinyl, carbazolyl, pyrrolyl, thiazolyl, isothiazolyl,
imidazolyl, benzothiophenyl, , and phenathridinyl; and where one to
five of the substituent(s) on the aryl or heterocyclyl being one or
more of halogen, or C.sub.1 to C.sub.8 alkyl, or alkenyl, or
hydroxyl, or C.sub.1 to C.sub.8 hydroxyalkyl, or C.sub.1 to C8
alkoxy, or C.sub.2 to C.sub.10 alkylcarbonyloxy, or C.sub.2 to
C.sub.10 carboxyalkyl or alkylcarboxyalkyl, or C.sub.3 to C.sub.10
alkylcarbonyloxyalkyl, or C.sub.2 to C.sub.8 acyl, or amino,
C.sub.1 to C.sub.8 alkylamino, or C.sub.2 to C.sub.10 acylamino, or
sulfonamido or C.sub.1 to C8 alkylsufonylamino, or
N-arylsulfonamido or N-heterocyclylsulfonamido and where the aryl
or heterocyclyl is selected from the group phenyl, benzyl, oxazoyl,
thiazoyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, and where the
aryl or heterocyclyl moiety is optionally substituted with a) up to
three C.sub.1 to C.sub.3 alkyl groups, b) up to three C.sub.1 to
C.sub.3 alkoxy groups, c) Cl to Cs aminoalkyl or diaminoalkyl, d)
C.sub.2 to C.sub.10 alkylaminoalkyl, e) C.sub.2 to C.sub.10
acylaminoalkyl, f) carboxy, or g) C.sub.2 to C.sub.10
alkylcarboxy.
7. The method as in claim 6 wherein the biologically active
compound is selected from the group consisting of
2-Isopropyl-5-methyl-cyclohexanecaboxylic acid
[2'-hydroxy-2'-(3''-hydroxy-phenyl)-ethyl]-N-methyl-amide,
2-Isopropyl-5-methyl-cyclohexanecarboxylic acid
[2'-(4''-acetyl-2''-hydroxymethyl-phenyl)-ethyl]-amide,
2-Isopropyl-5-methyl-cyclohexanecarboxylic acid
[2'-hydroxy-2'-(3''-hydroxy-phenyl)-ethyl]-N-methyl-amide, or
2-Isopropyl-5-methyl-cyclohexanecarboxylic acid
[2'-hydroxy-2'-(3''-hydroxy-phenyl)-ethyl]-N-methyl-amide.
8. The method as in claim 6 wherein the administration is
topical.
9. The method as in claim 6 wherein the administration is by
inhalation using a pressurized metering device.
10. The method as in claim 6 wherein from 0.1 to to 2% by weight of
the compound is topically applied.
11. The method as in claim 6 wherein the orally administered amount
provides about 0.001 to 0.2 grams of the compound per dose.
12. The method as in claim 6 wherein the delivery vehicle is an
enteric-coated capsule adapted to deliver the compound into the
gastrointestinal tract.
13. The method as in claim 6 wherein the therapeutically effective
amount of delivered compound alleviates itch, cough, or pain.
14. The method as in claim 6 wherein the sensory disorder is acute
or chronic pain.
15. The method as in claim 6 wherein the sensory disorder is
itching or coughing.
16. The method as in claim 6 wherein the sensory disorder is
inflammation and pain in the upper respiratory tract or in the oral
cavity.
17. The method as in claim 6 wherein the therapeutically effective
amount of delivered compound reduces pruritus caused by kidney
failure or by cholestatic jaundice.
18. A drug design method, useful to improve drug action duration,
comprising: providing a first molecule with a first, determinable
biological activity, the first biological activity due at least in
part to a pharmacophore unit of the first molecule; providing a
second molecule with a second, determinable biological activity,
the second biological activity being a direct or indirect acting
.alpha.-adrenergic receptor agonist action; and, conjugating at
least the pharmacophore unit of the first molecule with the second
molecule.
19. The drug design method as in claim 18 wherein the first
biological activity is as a coolant.
20. The drug design method as in claim 18 wherein the second
biological activity is as a vasoconstrictor.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefits of U.S. Provisional
Application 60/857897, filed Nov. 8, 2006. Inventor Wei:
"Compositions and Methods for Systemic Modulation of Sensory
Discomfort." This application is a continuation-in-part of Ser. No.
11/064,358, "N-Aryls-Carboxamide Compositions and Methods" filed on
Feb. 22, 2005, and published as US 2005/0187211 A1, Aug. 25, 2005,
which claims the benefits of U.S. Provisional Application No.
60/547,263, N-Aryls-Carboxamide Compositions and Methods" filed on
Feb. 23, 2004.
BACKGROUND
[0002] 1. Field
[0003] This disclosure generally relates to chemicals that affect
sensory processes. More particularly, this disclosure provides
peripheral sensory compositions that are useful in sensory
refreshment and alleviation of skin irritation, itch and pain.
These compositions have surprising pharmacokinetic properties that
allow a prolonged duration of pharmacological actions and may be
administered topically or systemically.
[0004] 2. Description of Related Art
[0005] About two to three decades ago a group of scientists
discovered novel compounds that have a physiological cooling action
on the skin. These were described in U.S. Pat. No. 4,193,936
(Watson et al., Mar. 18, 1980), U.S. Pat. No. 4,248,859 (Rowsell et
al, Feb. 3, 1981), U.S. Pat. No. 4,318,900 (Rowsell, Mar. 9, 1982)
and in a publication: H. Watson et al, New compounds with the
menthol cooling effect. J. Soc. Cosmet. Chem. 29: 185-200,
1978.
[0006] There are currently two major classes of drugs that act
peripherally to reduce perception of nociceptive signals in the
central nervous system; nociceptive signals being stimuli that
cause irritation, itch and pain. One class is the local
anesthetics, such as procaine and lidocaine, which inhibit
peripheral nerve conduction of nociceptive signals towards the
central nervous system. Another group is agents like aspirin and
ibuprofen that inhibit the synthesis of certain prostaglandins.
These prostaglandins when released by tissues during injury or
inflammation lower the threshold of firing of sensory nerve fibers
that respond to noxious stimuli. By "peripheral" is meant that the
target of the drug action is located outside the central nervous
system, that is, outside of the brain and spinal cord. By
"antinociceptive" is meant that the drug suppresses the psychical
and physiological perception of noxious stimuli.
[0007] The sensory fibers that code for thermosensation,
irritation, itch and pain are small-diameter sensory fibers called
AB and unmyelinated C fibers. They are also sometimes called
polymodal. When tissues are irritated, injured or inflamed, the C
fibers are especially activated. When the compounds of this
invention are used, cooling and cold sensations are activated
presumably by A.delta. afferents. These sensations have the net
effect of reducing perception of C fiber activated nociceptive
signals.
[0008] U.S. Pat. No. 6,919,348, "Therapeutic
1,2,3,6-Tetrahydropyrimidine-2-One Compositions and Methods
Therewith", issued Jul. 19, 2005 to Wei describes
1,2,3,6-Tetrahydropyrimidine-2-One compounds useful for itch. Other
molecules investigated by Wei are described in: US 2005/0059639,
published Mar. 17, 2005, Ophthalmic Compositions and Methods for
Treating Eye. Discomfort and Pain; US 2005/0159394, published Jul.
21, 2005, Aryl-Substituted Derivatives of Cycloalkyl and Branched
Chain Alkyl Carboxamides and Carboxylic Acids Useful as
Antinociceptive Drugs For Peripheral Targets; US 2005/018721 1,
published Aug. 25, 2005, N-Aryls-Carboxamide Compositions and
Methods; and WO 2006/103401, published Oct. 5, 2006,
N-Alkylcarbonyl-Amino Acid Ester and N-Alkylcarbonyl-Amino Lactone
Compounds and Their Use.
SUMMARY
[0009] In one aspect of the present discovery, compositions for
topical application are described here that have cooling and cold
effects that are useful to counteract sensory irritation, itch and
pain.
[0010] One preferred set of embodiments are compositions including
N-substituted-aryl-alkyl)cycloalkyl-carboxamides. These preferred
embodiments have the desirable quality of long duration of action
(more than I hour) when applied to the skin. Further
pharmacokinetic advantages are achieved with the
N-(substituted-aryl-hydroxyalkylidene)cycloalkyl-carboxamides in
formulations adapted for topical application.
[0011] In another aspect of this discovery, a drug design method,
useful to improve drug action duration, comprises providing a first
molecule with a first, determinable biological activity, and
providing a second molecule with a second, determinable biological
activity, the second biological activity being a direct or indirect
acting .alpha.-adrenergic receptor agonist action. These two
molecules are conjugated. The first molecule is preferably a
coolant, and the second molecule is preferably a
vasoconstrictor.
[0012] In yet another aspect, a method for treating sensory
discomfort is provided by topically administering a composition
having a biologically active compound carried by a delivery
vehicle, wherein the biologically active compound comprises a
N-(substituted-aryl-hydroxyalkylidene)cycloalkyl-carboxamide.
[0013] Other aspects of the present disclosure will be understood
by reading the following detailed description and the accompanying
claims.
BRIEF DESCRIPTION OF THE DRAWING
[0014] FIG. 1 graphically illustrates four composition embodiments
in accordance with this invention which produce cooling on the skin
of the upper lip with duration of action of more than 1 hr. The
structures of CPS-179, CPS-190, CPS-192, CPS-195 are shown in Table
4. Test substances were dissolved in warm Aquaphor.RTM. ointment,
applied to the upper lip, and coolness intensity was recorded and
plotted.
DETAILED DESCRIPTION
[0015] Introduction. Without being bound by theory, I believe that
compounds in compositions of the present disclosure act on sensory
processes in peripheral neurons to suppress perception of skin
irritation, itch and pain. In normal skin, these compounds generate
cooling, refreshing sensations. Embodiments are compounds with the
structures shown in Formula 1 R--CO--N(R'')--R'--Y Formula 1
where
[0016] a) R is (1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl,
[0017] b) R'' is hydrogen, methyl, ethyl, n-propyl, or
isopropyl
[0018] c) R' is a divalent C.sub.2 to C.sub.4 hydroxyalkylidenyl
radical,
[0019] d) Y is a substituted-aryl, or -heterocyclyl, [0020] where
the aryl or heterocyclyl includes phenyl, 1-naphthyl, indenyl,
azulenyl, heptalenyl, indacenyl, pyridinyl, dihydropyridinyl,
pyridazinyl, piperazinyl, pyrmidinyl, pyrazinyl, indolyl, purinyl,
indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl,
pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, benzothiophenyl, and
phenathridinyl; and [0021] where one to five of the substituent(s)
on the aryl or heterocyclyl being one or more of halogen, or
C.sub.1 to C.sub.8 alkyl, or alkenyl, or hydroxyl, or C.sub.1 to
C.sub.8 hydroxyalkyl, or C.sub.1 to C.sub.8 alkoxy, or C.sub.1 to
C.sub.10 hydroxyalkyl or polyhydroxyalkyl, or C.sub.2 to C.sub.10
alkylcarbonyloxy, or C.sub.2 to C.sub.10 carboxyalkyl or
alkylcarboxyalkyl, or C.sub.3 to C.sub.10 alkylcarbonyloxyalkyl, or
C.sub.2 to C.sub.8 acyl, or amino, C.sub.1 to C.sub.8 alkylamino,
or C.sub.2 to C.sub.10 acylamino, or sulfonamido or C.sub.1 to
C.sub.8 alkylsufonylamino, or N-arylsulfonamido or
N-heterocyclylsulfonamido and where the aryl or heterocyclyl is
selected from the group phenyl, benzyl, oxazoyl, thiazoyl,
pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, and where the aryl or
heterocyclyl moiety is optionally substituted with a) up to three
C.sub.1 to C.sub.3 alkyl groups, b) up to three C.sub.1 to C.sub.3
alkoxy groups, c) C.sub.1 to C.sub.8 aminoalkyl or diaminoalkyl, d)
C.sub.2 to C.sub.10 alkylaminoalkyl, e) C.sub.2 to C.sub.10
acylaminoalkyl, f) carboxy, or g) C.sub.2 to C.sub.10
alkylcarboxy.
[0022] The term "alkylidene" means a straight or branched
saturated, aliphatic, divalent radical having the number of carbon
atoms indicated. The carboxamide group is preferably in an
equatorial position relative to the plane of the cycloalkyl ring.
The aryl or heterocyclyl ring permits multiple radical insertions,
which increases the versatility of the ligand for its receptor. For
many applications, the form of a pharmaceutically acceptable salt
of the Formula compound is useful, such as wherein the salt is an
alkali or alkaline earth metal salt, an alkyl-substituted ammonium
salt, or a quaternary ammonium salt.
[0023] A novel feature of the structures described here is that R'
of Formula 1 is C.sub.2 to C.sub.4 hydroxyalkylidene and not a
hydrogen. By hydroxyalkylidene, I mean a divalent
hydroxyl-substituted, straight or branched saturated hydrocarbon
chain with 2 to 4 carbon atoms and of molecular formula
--C.sub.nH.sub.2nO--, where n is 2, 3 or 4. The consequence of this
feature is a more prolonged duration of topical action.
Compositions described by Watson et al. vide supra when applied
directly to the skin in a single dose generally act for less than 1
hour. By contrast, the chemicals described here, when applied once
topically, have actions that can last for three to six hours or
more.
[0024] Two examples of compounds of Formula 1 are illustrated as
Formulas 1A and 1B: ##STR1##
[0025] Formula 1A, Left Panel:
2-Isopropyl-5-methyl-cyclohexanecarboxylic acid
[2'-hydroxy-2'-(3''-hydroxy-phenyl)-ethyl]-N-methyl-amide, coded
CPS-195. Formula 1B, Right Panel:.
2-Isopropyl-5-methyl-cyclohexanecarboxylic acid
[2'-(4''-acetyl-phenyl)-3'-hydroxy-propyl]-amide, coded CPS-179.
Other examples of such compounds are where the p-menthoyl moiety is
conjugated an .alpha.-adrenergic receptor vasoconstrictor agonist
or to a phenylethanolamine or a phenylpropanolamine derivative that
indirectly releases norepinehrine from nerve endings and exert a
vasoconstrictor effect. These .alpha.-adrenergic vasoconstrictor
substances include ephedrine, epinephrine, phenylephrine,
methoxamine, metaraminol, .alpha.-methylnorepinephrine,
norepinephrine, octopamine, phenylethanolamine,
phenylpropanolamine, pseudoephedrine, and synephrine (see Table
1).
Use of N-(Substituted-Arylhydroxyalkylidene)-Cycloalkyl
Carboxamides
[0026] Hypothesis on Refreshment and Relief of Sensory Discomfort
and Novelty. I believe that the
N-(substituted-arylhydroxyalkylidene)-cycloalkyl carboxamides),
abbreviated here as N-aryl.sub.shydroxyalkylidene-cCarboxamide, and
synonymous with cycloalkyl carboxylic acid-aryl-R'-substituted
amide, where R' is hydroxylalkyl (and the corresponding terminology
is either the phenyl-alcohols or as phenylhydroxyethylamide,
phenylhydroxypropylamide) act on ion channel receptors to stimulate
discharge of peripheral sensory neurons. The class of ion channel
receptors may belong to the TRP (transient receptor potential)
family of proteins that mediate the effects of cooling on sensory
neurons (TRP-M8, TRP-A1). But the precise identities of such
receptors have not yet been established. When the nerve fibers,
most likely A.delta. cold fibers, relay signals to the spinal cord
and brain, these signals generate sensations of coolness and
refreshment. If pathological conditions are present, these signals
also suppress perception of signals for tissue irritation, for
pruritus, and for acute and chronic pain.
[0027] Without being limited by theory an analogy of operation is
as though there were three telephone lines in the tissues, each
with a different dialing mechanism and cable conduction system. One
is for touch and pressure that is fast conducting. One for coolness
and cold that is somewhat slower (A.delta. conducts at about 2 to 6
meters/sec). One for irritation, itch and pain that conducts slowly
(<2 meters/sec, primarily C-fibers). It is known that
acupuncture and scratching may relieve pain and itch via vibration
and pressure, respectively, and that this process takes place at
the level of the spinal cord (the so called "gate-control theory of
pain"). In the analogy, one of two telephone lines interferes with
the signaling of the other, but at the central exchange. Continuing
the analogy of this disclosure, I propose the use of compounds of
this discovery as the dialing mechanism for stimulating the
telephone line responsible for signals of coolness and cold. Using
this new telephone line, I anticipate refreshing and cool signals
to be generated and, in the presence of inflammation and injury, an
antinociceptive effect is achieved that has sensory benefit.
[0028] The compounds of this discovery are active at .mu.g to mg/mL
(nano to microM) concentrations when applied to the topical
surfaces of the body. By topical I mean that the application is
onto surfaces of the body in contact with air, which includes the
skin, the eye surface, the upper and lower respiratory tract, and
the entrance and exit of the gastrointestinal tract, that is, the
oral cavity and the anorectum. A second feature of these compounds
is a longer duration of action, on the order of several hours,
relative to compounds such as (-)-menthol and WS-5, which are
active for less than one hour. The longer duration of action was
discovered by using a bioassay: application of the test compounds
to the skin of test subjects, and not by using taste thresholds for
coolness or by using in vitro receptor assays.
Bioassays for activity of
N-(Substituted-Arylhydroxyalkylidene)-Cycloalkyl Carboxamides
[0029] Tests for Activities of New Compounds. Pain was defined by
Sir Charles Sherrington as "the psychic adjunct of an imperative
protective reflex". Psychic events such as cooling, irritation,
itch, and pain cannot be expressed by animals (animals cannot say
"ouch" or that "it itches") so the sensory effects of chemicals
must be indirectly inferred. Receptor assays, based on cells
transfected with the gene for TRP-M8 or TRP-A1, may be used as a
model of sensory processes. These data, such as EC50 (median
effective concentration for producing a half-maximal response), are
precise: but, as noted below, these assays give no information on
how long and for what quality of sensations is occurring on human
subjects. The best information on the pharmacological properties of
these chemicals must therefore be derived from human
experiment.
[0030] In humans, Rowsell et al. tested the properties of
N-aryl.sub.s-cCarboxamide by putting filter paper (1.times.1 cm),
impregnated with a known amount of compound onto the dorsal surface
of the tongue of the test subject. After 30 sec, the subject was
required only to report presence or absence of a cooling effect.
These data were reported as threshold values in .mu.g of test
substance.
[0031] I have found that the cooling and sensory properties of a
given compound, including the
N-aryl.sub.shydroxyalkylidene-cCarboxamide of this discovery, may
be best obtained by suspending or dissolving a test substance in an
ointment (usually Aquaphor.RTM. ointment which is 41% petrolatum,
and the rest mineral oil, ceresin and lanolin alchol) and applying
the emulsion (e.g. 0.2 to 0.5 cc) onto the skin surface. A reliable
place for topical application is on the upper lip, above the
vermillion border of the lips, on the philtrum, lateral to the
philtrum until the nasolabial folds, and on the lower nostrils.
This part of the face is known to be densely innervated with cold
receptors, second only to the surface of eyeball. Tingling, cool
and cold sensations may be experienced and rated for intensity.
This test is quite accurate for predicting the cooling activity of
candidate N-arylshydroxyalkylidene-cCarboxamide drugs, but most
importantly, it also measures the duration of drug action on the
sensory receptors. The duration of action is not measured in a
receptor assay and is difficult to quantify on the tongue because
of the dynamic fluid conditions in the oral cavity and the presence
of taste factors that affect thermosensation.
[0032] Qualitative Aspects of Cool and Cold Intensity. The
temperature of the skin and its environs gives rise to sensations
that are qualitatively distinct. Thus, the normal skin temperature
is 93.degree. F. (33.9.degree. C.) and when water is applied to the
skin it is called tepid at 80 to 93.degree. F. (26.7 to
33.9.degree. C.); cool between 65 to 80.degree. F. (18.3 and
26.7.degree. C.), cold at 55 to 65.degree. F. (12.8 to 18.3.degree.
C.), and very cold below 55.degree. F. (12.8.degree. C.) [Bierman:
Therapeutic Uses of Cold. J. Amer. Med. Assoc. vol. 157, 1189-1192,
1955]. The lowering of skin temperature is accompanied by
behavioral and emotional responses. Thus, at room temperatures at
or below 65.degree. F., an individual frequently seeks to turn on
the thermostat. At ambient skin temperatures at or below 55.degree.
F., the sensations are aversive and accompanied by affect; that is,
the person considers these cold sensations to be unpleasant, seeks
to escape the environment, and may become angry, hostile, or
malaised if escape is not possible. The emotional response is also
influenced by the circumstances and the site of exposure. For
example, ice cream inside the mouth is not aversive on a short-term
basis, but an ice cube placed on the skin for more than few minutes
is unpleasant. On the other hand, breathing cool air between 65 to
80.degree. F. is refreshing and alerting, especially if there is
inflammation in the upper respiratory tract or if the skin
temperature is elevated above normal.
Structure-Activity Relationships.
[0033] I have found the N-aryl.sub.s-cCarboxamide, CPS-112 (also
known as WS-12), with a 4-methoxy-substitution on the phenyl ring,
is active at sub-micromolar concentrations on the TRP-M8 receptor
assay. This compound elicits strong cold sensations when applied at
1 to 2% to the philtrum and its environs. The sensations are more
cold than cool, and have the sting and harshness of high
concentrations of menthol. The duration of action of a 2%
preparation peaks at 30 min and is dissipated at the end of one
hour. CPS-112 was therefore a disappointment in spite of its high
potency on the receptor assay.
[0034] For topical uses, either as a cosmetic or as a therapeutic,
it is desirable to have more coolness than cold, more cold than
intense cold, and to have a duration of action that permits a
practical application. For example, in cosmetic use, if the added
compound is used to reduce the irritation produced by retinoids or
.alpha., or .omega.-fatty acids, then the duration of action should
be at least three hours. The sensation should be of coolness and
not of cold. These qualitative aspects of sensation are met by
CPS-116 and CPS-125, but not by CPS-112 which produced sensations
of cold, but of brief duration. If the ointment is to have
therapeutic value in the pruritus caused by xerosis in the elderly,
in atopic eczema, or in perianal inflammation, then the duration of
action is preferably more than six hours. Again, the philtrum
method of testing gives an answer for the duration of action and
the quality of sensation which is not obtainable with the tongue
threshold or in vitro receptor methods.
Method for Drug Design
[0035] To further improve duration of drug action in practicing
this discovery, two design features were conceived and then
implemented. One was to link the pharmacophore (defined as the
functional unit on the molecule responsible for its drug action) to
a vasoconstrictor element that will reduce diffusion of the coolant
portion of the molecule away from its site of action. A second
design feature was to use computer database software to predict
distribution and safety of the molecule after structural
modifications. A satisfying result of these ideas was the finding
that the substitution of a hydroxyalkylidene group for the
alkylidene group in the N-aryl.sub.salkyl-ccarboxamide
significantly improved the duration of action and reduced
penetration into the brain.
[0036] For the first concept, in one set of the inventive
embodiments, I have coupled the coolant portion of the molecule,
residing in the p-menthane carbonyl group, to a
phenylhydroxyalkylamine unit that has actions on blood vessels.
Substituted phenylalkylamines and phenylhydroxyalkylamines are
substances used for controlling blood vessel diameter and encompass
molecules such as norepinephrine, epinephrine, ephedrine,
isoproterenol, metaraminol, methoxamine, and phenylephrine. These
compounds encompass .alpha.-adrenergic receptor agonists and
substances that release norepinephrine from nerve endings and are
collectively called sympathomimetic drugs because they mimic the
actions of stimulation of the sympathetic nervous system. These
compounds are listed, for example, in standard texts such as
Goodman and Gilman, Pharmacological Basis of Therapeutics,
11.sup.th Edition, Brunson et al. editors, Table 10-1, "Chemical
structures and main clinical uses of important sympathomimetic
drugs", pg. 240-241.
[0037] Table I illustrates some suitable .alpha.-adrenergic
receptor agonists, which can then be coupled, or conjugated by
N-acylation with a coolant, such as 2-Isoproply-5-methyl
cyclohexanecarboxylic acid, to produce cooling agents with very
long durations of action. TABLE-US-00001 TABLE 1 Structures of some
suitable sympathomimetic drugs that act as .alpha.- adrenergic
receptor agonists. ##STR2## Chemical Name R1 R2 Y.sub.1, Y.sub.2
Epinephrine CH.sub.3 H 3',4'-diOH Norepinephrine H H 3',4'-diOH
Metaraminol H CH.sub.3 3'-OH Phenylephrine CH.sub.3 H 3'-OH
Methoxamine H CH.sub.3 2',5'-diOCH.sub.3
.alpha.-Methylnorepinephrine H CH.sub.3 3',4'-diOH Ephedrine
CH.sub.3 CH.sub.3 H, H Octopamine H H 4'-OH Synephrine CH.sub.3 H
4'-OH Pseudoephedrine* CH.sub.3 CH.sub.3 H, H Phenylpropanolamine*
H CH.sub.3 H, H Isoproterenol** (CH.sub.3).sub.2--CH-- H 3',4'-diOH
* = indirect acting sympathomimetic ** = an .alpha.-and
.beta.-adrenergic receptor agonist diOH = dihydroxy diOCH.sub.3 =
dimethoxy
[0038] The use of vasoconstriction to limit distribution and
restrict the actions of local anesthetics on sensory fibers is
known in pharmacological practice. Thus, to obtain nerve block with
a local anesthetic, such as used in dentistry, epinephrine is
co-injected with procaine to limit the diffusion of the procaine
into the bloodstream. Cocaine is sometimes preferred to procaine in
nasal membrane surgery because cocaine also inhibits the neuronal
re-uptake of norepinephrine, and hence cocaine has a dual action,
local vasoconstriction and anesthesia, resulting is less blood loss
during surgery. In the case of cocaine, vasocontrictive and local
anesthetic properties are present in the same molecule. This
concept of dual activity, however, has never been applied to design
and produce a molecule with both coolant and vasoconstrictive
properties.
[0039] Thus, in the case of CPS-195, where p-menthoyl chloride is
conjugated to L-phenylephrine to form
2-Isopropyl-5-methyl-cyclohexanecaboxylic acid
[2'-hydroxy-2'-(3''-hydroxy-phenyl)-ethyll-N-methyl-amide, the goal
was to obtain a compound with prolonged cooling/antinociceptive
action because a) the parent is bioactive, b) the metabolites are
also bioactive. The metabolite
2-isopropyl-5-methyl-cyclohexanecaboxylic acid (WS-1) is known to
have mild cooling activity, and the second metabolite,
L-phenylephrine, is a potent vasoconstrictor. The result was a
compound with a surprisingly long duration of action--on the order
of 4 hr after a single dose of 2 mg applied to the surface of the
tongue or on to the philtrum (see Example 5).
[0040] An additional advantage of CPS-195, from a toxicological
viewpoint, is that the pathways of phenylephrine (syn.
m-synephrine) metabolism in humans are known. Thus, phenylephrine
is converted to m-hydroxymandelic acid, m-hydroxyphenylglycol, and
phenylephrine sulfate and phenylephrine glucuronide. This increases
knowledge about the safety of the molecule because its potential
metabolites have been characterized.
[0041] In the second concept, the importance of the
hydroxyalkylidene group on access and residence of the agonist
molecule at the target sites was analyzed. A key pharmacokinetic
determinant of drug distribution and delivery on the skin is the
octanol/water partition coefficient. Thus, the log of the
octanol/water partition coefficient (log P) in the range of 2.0 to
4.0 is considered ideal for activation of cool receptors in the
skin and mucous membranes. For a systemic antinociceptive agent,
the range is more restrictive, in the range of 2.5 to 3.5, because
it is not desirable for the drug to cross the blood-brain-barrier
(BBB). Sophisticated ADMET analysis programs, such as are available
from Simulation-Plus (Lancaster, Calif.) can predict drug passage
across the BBB, based on the parameters described by Crivori et al.
"Predicting blood-brain barrier penetration from molecular
structure." J. Med. Chem 43: 2204-2216, 2000. In the examples,
compounds were selected based on a low likelihood of passage across
the BBB.
[0042] An analysis of the structure-activity relationships from the
present studies indicates that the presence of a hydroxyalkylidene
group, preferably hydroxymethylidene or hydroxyethylidene, on
N-substituted-p-menthane-carboxamides confers the desirable quality
of low penetration across the BBB yet retaining cooling activity.
The presence of polar entities on the molecule in the addition to
the hydroxyalkylidene group, e.g. hydroxyl or carboxyl or
sulfonamido, also contributes to desirable ADME (absorption,
distribution, metabolism, excretion) properties that will permit
use as a systemic agent and yet reduce penetration of the BBB. This
analysis of ADME properties is a preferred mode of practicing
aspects of this discovery and these ADME properties were determined
by programs designed to simulate and model pharmacokinetic
parameters of ideal drug candidates.
Delivery and Therapeutic Uses of
N-Aryls.sub.shydroxyalkylidene-cCarboxamide Embodiments
[0043] In practicing this discovery the
N-aryl.sub.shydroxyalkylidene-cCarboxamide compounds are
incorporated into topically suitable formulations, applied
topically to inflamed skin and mucous membranes, and will typically
relieve itch, irritation and pain. By "topical" is meant
application onto surfaces of the body in contact with air, which
includes the skin, the eye surface, the upper and lower respiratory
tract, and the entrance and exit of the gastrointestinal tract,
that is, the oral cavity and the anorectum. Suitable topical
formulations, for example, include compositions such as powders,
pastes, lotions, liniments, creams and ointments, and cosmetic
preparations.
[0044] In formulating topical compositions to practice this
discovery, the N-aryl.sub.shydroxyalkylidene-cCarboxamide may be
incorporated into a vehicle that by itself may be inert or may
contain other active ingredients (e.g. a flavor or a
glucocorticosteroid). A wide variety of vehicles will be suitable,
depending upon the particular product involved, such vehicles
including solids, liquids, propellants, emulsions, foams and gels.
Typical vehicles include oils and fats such as hydrocarbon oils,
fatty acid esters, long chain alcohols and silicone oils; finely
divided solids such as starch or talc; low-boiling hydrocarbons;
gums and natural or synthetic resins. For applications to the
ocular surface or to the upper or respiratory tract, the compound
may be packaged in unit dose dispensers. For the lower respiratory
tract a pressure activated metered dosage inhaler or nebulizer may
be used.
[0045] Therapeutic indications for which a topical formulation may
be beneficial include irritation, itch and pain from various forms
of dermatitis (atopic, contact and irritant); pain from burned,
traumatized or irritated skin, from procedures related to wound
debridement; itch and discomfort from from skin infections, insect
bites, sunburn, actinic keratoses, basal cell carcinoma, pruritus
due to xerosis; cheilitis or itching of the lips from cold sores;
pruritus ani, hemorrhoidal discomfort, pain from anal fissures,
pain or itch from anal fistulas, pain from hemorrhoidectomy,
perineal inflammation, anogenital skin inflammation and discomfort
due to various local causes such as incontinence, diaper rashes,
perineal inflammation; vulval pruritus and pain (e.g. from
candidiasis or idiopathic, such as vulva vestibulitis and
vulvodynia), dyspaurenia, anogenital infections, including warts
and sexually transmitted diseases, viral infections of the skin
(especially in immunocompromised patients); nostril and nasal or
upper airway discomfort from breathing obstruction, e.g. rhinitis,
asthma, bronchitis, emphysema and chronic obstructive pulmonary
diseases, sleep apnea and snoring; conjunctivitis, pain from
corneal abrasions, and pain from eye surgery.
[0046] The use of the inventive embodiments in an asthma medication
is of special interest because a primary pathogenic process in
asthma, hyperresponsiveness of airways, may be susceptible to an
agent that affects sensory processes. Thus, an agent such as
CPS-195, may be incorporated into an inhaled medication and
delivered via a pressurized-metering dose inhaler (a standard form
of delivery for asthma medications). The inventive embodiment may
be the sole active ingredient or incorporated together with an
anti-inflammatory corticosteroid, a bronchial smooth muscle
relaxant and/or an antimuscarinic agent.
[0047] If the target is to be reached via the bloodstream, an oral
formulation is designed to be optimally absorbed from the
gastrointestinal tract and to achieve steady blood or plasma
levels. Here again, a simple gelatin capsule or an enteric coated
pill or capsule, designed for optimum dissolution at a given pH, is
a familiar formulation to practitioners skilled in the art.
Extensively used chemicals for enteric coating are cellulose
acetate phthalate, methacrylic acid ester copolymers with acidic
ionizable groups, and polyvinyl acetate phthalate. Standard coating
ingredients are widely sold under the trademark of Eudragit.RTM.
(Degussa Chemicals, Inc.). Dosage forms coated with methacrylic
acid polymers dissolve in the ileum at about pH 6.8, and in the
terminal ileum and caecum at about pH 7.2. In general coating
thicknesses of about 25 to 200 microns, and especially 75 to 150
microns, are preferred using about 3 to 25 mg, preferably 8 to 15
mg of acidic coating material per square centimer of tablet or
capsule surface. The precise coating thickness will however depend
upon the solubility characteristics of the material used and the
site to be treated.
[0048] Therapeutic indications for which a systemic formulation may
be beneficial include irritation, itch and pain from various forms
of pathology. For example, systemic pruritus occurs frequently in
patients undergoing renal dialysis and in patients with certain
forms of liver failure. It is believed that certain endogenous
substances (e.g. enkephalin peptides, bile acids) are not
adequately cleared or released during kidney or liver dysfunction
and these substances then act on nerve endings to produce
generalized itching. Current pharmacotherapy with opioid
antagonists such naltrexone, peripheral kappa-opioid receptor
agonists such as nalfurafine, substance P antagonists such as
odsanteron, cannabinoid receptor agonists, antihistamines and other
chemicals are of limited effectiveness in treatment. The rationale
in this application is to use compounds with cooling properties, to
deliver these agents into the bloodstream, and to target receptors
on sensory nerves and epithelium, in order to reduce noxious
sensory perception.
[0049] Additional Applications. The
N-aryls.sub.shydroxyalkylidene-cCarboxamide compositions described
here have the desirable properties of non-irritancy, safety and
long duration of action. Uses of a formulation containing the
inventive embodiments would include conditions such as heat
exhaustion and fatigue, nasal and eye irritation, obstructed
breathing disorders, lower urinary tract disorders, heartburn,
irritable bowel disease or the irritable bowel syndrome,
generalized pruritus, and systemic pain. Itch and pain are common
sensory discomforts associated with various disorders, a list
wherein said active agent is intended for the treatment of a
disorder would include and be selected from the group consisting of
contact dermatitis, atopic dermatitis, seborrheic dermatitis,
chronic dermatitis of the hands and feet, exfoliative dermatitis,
stasis dermatitis; lichen simplex chronicus; diaper rash; bacterial
infections including erysipelas, cutaneous abscesses, necrotizing
subcutaneous infections, folliculitis, furuncles, hidradenitis
suppurativa, carbuncles, paronychial infections, erythrasma; fungal
infections including dermatophyte infections, yeast infections;
parasitic infections; viral infections, disorders of hair follicles
and sebaceous glands, acne, rosacea, perioral dermatitis; scaling
papular diseases, psoriasis, pityriasis rosea, lichen planus,
pityriasis rubra pilaris, benign tumors, moles, seborrheic
keratoses, keloid; malignant tumors, basal cell carcinoma, squamous
cell carcinoma, malignant melanoma, Kaposi's sarcoma; reactions to
sunlight, sunburn, photosensitivity; pemphigus, vitiligo, albinism,
drug-induced hyperpigmentation, ichthyosis, corns, actinic
keratosis; pressure sores, erythema multiforme, erythema nodosum.
Included are non-dermatological disorders, which respond to
topical/transdermal/oral delivery of an active agent, such as
localized pain, generalized pain, nociceptive pain, neuropathic
pain, joint pain, muscle pain, back pain, cardiac pain, rheumatic
pain, arthritis, ostheoarthritis, acute soft tissue injuries and
sports injuries, pelvic pain, premenstrual syndrome (PMS),
dysmenorrhea, endometriosis, and vulvodynia, candidal vaginitis,
herpes simplex, genital ulcers and warts, dyspareunia and
vaginismus, anal abscess/fistula, anal warts, inflammatory bowel
diseases, Crohn's disease, hemorrhoids, perianal thrush, anal
fissures, sexually-transmitted disease and non-sexually-transmitted
vaginal and genital infectious disease.
Experimental
[0050] Aspects of the discovery will now be illustrated, without
intending any limitation, by the following examples.
EXAMPLE 1
[0051] N-Acylated carboxamides can be synthesized by reacting a
carboxylic acid with thionyl chloride and then conjugating the acid
chloride to the appropriate amine. This is a general chemical
procedure familiar to the practioners of the art and can be
accomplished without undue experimentation. In preparing a
conjugate of this discovery shown by Formula 1, the carboxylic acid
chosen, for example, may be
(1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexanecarboxylic acid, the
preferred enantiomer. This chemical is also known as WS-1 and may
be synthesized from 1-menthol or purchased from commercial firms.
WS-1 may be reacted with thionyl chloride to form the reagent
p-menthoyl chloride, or it can be reacted directly in situ with the
desired amine conjugate (that is, the vasoconstrictor). The
resulting conjugated product shown by Formula 1, usually a white
crystalline solid, may then be purified by column chromatography
and isolated by solvent evaporation. These are standard procedures
of the organic chemistry laboratory.
[0052] Many substituted arylhydroxyalkylamines may be obtained from
commercial sources such Sigma-Aldrich Corp., St. Louis, Mo. For
example, phenylephrine HCl, metanephrine HCl, isoproterenol HCl,
norepinephrine HCl, and octopamine HCl are listed in the 2005-2006
Aldrich Catalog. The acid chloride is reacted with the appropriate
arylhydroxyalkylamine to form the desired
N-aryls.sub.shydroxyalkylidene-cCarboxamide.
EXAMPLE 2
Synthesis of 2-Isopropyl-5-methyl-cyclohexanecaboxylic acid
[2'-hydroxy-2'-(3''-hydroxy-phenyl)-ethyl]-N-methyl-amide
[0053] L-Phenylephrine HCl
[(R)-(-)-3-(1-Hydroxy-2-methylamino-ethyl)-phenol. hydrochloride]
was purchased from Aldrich Chemicals, Co., Milwaukee, Wis. 1.0 g
was dissolved in 28 ml diethyether and 1 ml double-distilled water
and cooled to 0.degree. C. A pinch of the catalyst
diaminopyrimidine was added. 1.90 ml of p-menthoyl chloride was
then added dropwise, followed by 2 ml of triethylamine. Clumps of
white precipitate appeared in the mixture, which was stirred
overnight at room temperature. The precipitate was dissolved with
ethylacetate, washed with double-distilled water and dried over
sodium sulfate. The organic phase was then evaporated under reduced
pressure to yield the final product (1.8 g), which crystallized at
room temperature. The expected molecular mass was then confirmed by
mass spectroscopy and the absorption spectrum by nuclear magnetic
resonance. This compound was given the code of CPS-195.
[0054] Bioassay Procedures For bioassay of CPS-195 on the skin,
CPS-195 was stirred and dissolved in warm liquid Aquaphor.RTM.
ointment to yield ointment concentrations of 0.25, 0.5, 1 and 2%
wt/vol. After cooling, 50 to 80 mg of the solid ointment was placed
on the tip of a plastic stick and applied to the skin above the
upper lip, on the philtrum, and lateral to the philtrum up to the
nasolabial folds, of test subjects and the onset and duration of
cooling sensations recorded. Similarly, CPS-179, CPS-190, and
CPS-192 were formulated and tested, and the results are shown in
FIG. 1.
[0055] The intensity of the subjective skin sensation is rated as
0, 1, 2 or 3 with: 0 as no change, 1 as slight coolness, cold, or
tingling, 2 as clear cut signal of coolness, cold, or tingling, and
3 as robust cooling or cold. The interval for recording sensations
is at 5 min intervals, until two successive zeroes are obtained.
The results are averaged values of 4 to 6 separate trials in the
same individual. The data are plotted using SigmaPlot (Systat
Software, Point Richmond Calif.) and a smoothing function with a
negative exponential was used for analysis and statistical fit of
the results.
[0056] The onset of drug action is taken as the time to reach 2
units of coolness intensity, and offset of drug action is the time
when coolness intensity drops below 1.5, after previously
surpassing 2 units. The duration of cooling action is defined as
the offset time minus the onset time, which in this case averaged 2
min. The quality of the sensation is also noted, such as refreshing
coolness, cold, or if the sensation is accompanied by irritation
(stinging or burning). The quality of the sensation is not rated
for intensity.
[0057] CPS-195 produces sensations of coolness and cold on the skin
of the upper lip with duration of action of 1.2, 1.8, 2.4 and 5.2
hr for the four concentrations (0.25, 0.5, 1 and 2 %) tested.
Compared to CPS-179, CPS-190, and CPS-192 it was the most
potent.
[0058] Placement of 2 mg of CPS-195 on the dorsal surface of the
tongue resulted in a pleasant cooling sensation within the oral
cavity that lasted for the surprisingly long period of over 4
hours. The onset of cooling was 3 to 5 min, but once the effect was
established, the entire oral cavity and pharyngeal surfaces (oro-,
laryngo- and naso-pharynx) felt cool. No significant tastes, such
as bitterness or saltiness, were associated with CPS-195 and the
cool/cold sensations were pleasant and not aversive.
[0059] CPS-195 was formulated as a 3% wt/wt tablet in
Ludipress.RTM., a rapidly disintegrating direct compression
excipient made by BASF Corp. The tablet size was 60 mg so each unit
contained 1.8 mg of CPS-195. In normal individuals, this tablet
placed on the surface of the tongue produced the effects as
described in the previous paragraph for the powder. In an
individual with throat irritation and cough, the CPS-195 tablet
reduced throat irritation and had an antitussive effect that lasted
for 24 hr. The prolonged action of CPS-195 tablet was unusual and
indicated that it had multiple applications in therapy. For
example, applied onto the mucous membranes of the oral cavity it
can soothe the discomforts of pharyngitis/laryngitis, oral
mucositis, oral ulcers, and idiopathic facial pain. In the pharynx
and upper airways, CPS-195 may be used to reduce or to treat cough,
asthma, and chronic obstructive pulmonary disease. On the skin,
CPS-195 can be used to treat the discomfort of severe acne, eczema,
diabetic ulcers, and the like.
[0060] The ADME parameters of CPS-195 were computed and the results
showed that it is a suitable candidate to be a topical or systemic
antinociceptive drug. No toxicity is expected to occur, as
phenylephrine (part of the conjugate) is a known over-the-counter
medication used as a vasoconstrictor for the eye surface and as a
decongestant on the nasal membranes. The synthesis of CPS-195,
depending on the starting substrate, can generate two enantiomers
with respect to the asymmetric carbon in the alkylidene group
(--R'--). The herein-described drugs are meant to encompass, where
applicable, any and all enantiomers, mixtures of enantiomers
including racemic mixtures, solvates, different physical forms
(e.g., crystalline solids, amorphous solids), metabolites, and the
like.
[0061] The optically pure .alpha.-adrenergic agonists and other
sympathomimetics are known and described in the art, for example,
by Patil et al. (Molecular geometry of adrenergic drug activity,
Pharmacological Reviews 26: 326-392, 1975) and by Booth and
Caffrey. Stereoisomers with high affinity for adrenergic receptors.
U.S. Pat. No. 6,664,424 (Dec. 16, 2003). Other compounds
contemplated for conjugation with p-menthoyl chloride include
octopamine, methoxamine, metanephrine, pseudoephredrine, and such
entities as t-butyl-4-aminobenzoate,
(R)-(-)-t-butylamino-1-phenylethanol, and
(S)-(+)-t-butylamino-1-phenylethanol, all of which are available
from Aldrich Chemical Co.
EXAMPLE 3
[0062] A number of compounds were synthesized or simulated to
ascertain the importance of adding a hydroxylalkylidene group to
pharmacokinetic parameters. Several programs were used for
simulation, including a log P program designed for the College of
Chemistry at the University of California at Berkeley. The data in
Table 2 to 4 were based on the ADME analysis programs from
Simulation-Plus (Lancaster, Calif.). This program uses the
parameters described by Crivori et al. "Predicting blood-brain
barrier penetration from molecular structure." J. Med. Chem 43:
2204-2216, 2000 for estimating drug passage across the BBB.
Comparison of the data in Table 2 for compounds either having or
not having a hydroxylalkyl groups showed that the addition of a
hydroxyalkyl increases water solubility, lowers log P, and reduces
the likelihood of passage of the molecule across the
blood-brain-barrier. TABLE-US-00002 TABLE 2 Hydroxyalkyl
substituents on R2 in various molecules reduce penetration of the
blood-brain-barrier. R--CO--NH--R1--C(.dbd.O)--O--R2 Water BBB Code
R1 R2 LogP solubility entry WS-31 --CH.sub.2-- --CH.sub.3 2.66 0.44
high WS-5 --CH.sub.2-- --CH.sub.2--CH.sub.3 3.07 0.21 high CPS-368
--CH(CH.sub.3)--* --CH.sub.3 3.12 0.20 high CPS-337 --CH.sub.2--
--CH.sub.2--CH.sub.3 3.39 0.29 high CPS-338 --CH.sub.2CH.sub.2--
--CH.sub.2--CH.sub.3 3.40 0.12 high CPS-369 --CH(CH.sub.3)--*
--CH.sub.2--CH.sub.3 3.76 0.07 high CPS-153 --CH(CH.sub.3)--*
--CH.sub.2--CH.sub.2OH 2.27 0.68 low CPS-154 --CH(CH.sub.3)--*
--CH.sub.2--CH.sub.2--CH.sub.2OH 2.67 0.75 low CPS-155
--CH(CH.sub.3)--* --CH.sub.2--CH.sub.2--CHOH--CH.sub.3 3.12 0.82
low CPS-156 --CH(CH.sub.3)--*
--CH.sub.2--(CH.sub.2).sub.2--CH.sub.2OH 3.14 0.82 low = The
.alpha.-carbon of these compounds is in the D-conflguration. BBB =
brain-brain-barrier, Water solubility = mol/L, logP = log
octanol/water partition coefficient. These parameters were obtained
using a commercial computer analysis program for ADMET
prediction.
EXAMPLE 4
[0063] The presence of a phenyl group increases the log P, reduces
water solubility and most compounds readily cross the BBB (Table
3). The presence of an acidic function, such as a sulfonic acid or
a salicylic acid will increase protein binding and reduce entry
into the brain; however, such acidic fimctions lower biological
activity. CPS-125, a sulfonamide, has the desired properties of
good biological activity and absence of penetration of the BBB. The
presence of a hydroxyalkyl function on the phenyl, together with
another polar function such as either acetyl or hydroxyl will
reduce passages across the BBB. On the other hand, the methoxy
fimction is not sufficiently polar to prevent passage.
TABLE-US-00003 TABLE 3 Hydroxyalkyl substituents on the phenyl ring
in some structures reduce entry past the blood-brain-barrier.
R--CO--NH--Y, where Y = phenyl Water BBB % protein Code
Substituents on Y logP solubility entry bound CPS-152
4'--CH.sub.2SO.sub.3H 2.71 0.500 low 93 CPS-146 2'-OH,
4'-C(.dbd.O)--NH.sub.2 3.06 0.068 high 49 CPS-129 3'-OH,
4'-SO.sub.2NH-pyrmidine 3.64 0.022 low 89 CPS-131 2'-CH.sub.2OH,
4'-C(.dbd.O)--CH.sub.3 3.10 0.050 low 64 CPS-132 2'-OH,
4'-CH.sub.2OH 3.15 0.110 low 48 CPS-133 3'-CH.sub.2OH,
4'-O--CH.sub.3 3.46 0.070 high 64 CPS-134 4'-CH.sub.2OH 3.58 0.050
high 68 CPS-141 3'-OH, 4'-C(.dbd.O)--CH.sub.3 3.68 0.013 high 53
CPS-147 4'-SO.sub.3--CH.sub.3 3.71 0.088 high 62 CPS-140
4'-C(.dbd.O)--CH.sub.3 3.85 0.010 high 68 CPS-125
4'-SO.sub.2NH-pyrimidine 3.86 0.017 low 96 CPS-149 2'-OH,
4'-C(.dbd.O)--OH 4.31 0.052 low 88 CPS-309 2'-O--CH.sub.3,
4'--O--CH.sub.3 4.34 0.006 high 50 WS-12 4'-O--CH.sub.3 4.39 0.008
high 68 CPS-306 4'-O--CH.sub.2--CH.sub.3 4.85 0.004 high 70 CPS-111
4'-C(.dbd.O)--OCH.sub.2--CH.sub.3 4.90 0.004 high 67 CPS-310
4'-O--(CH.sub.2).sub.2--CH.sub.3 5.39 0.002 high 72 CPS-308
4'-O--(CH.sub.2).sub.3--CH.sub.3 5.93 0.001 high 74 BBB =
brain-brain-barrier, Water solubility = mol/L, logP = log
octanol/water partition coefficient. These parameters were obtained
using a commercial computer analysis program for ADMET
prediction.
EXAMPLE 5
[0064] As shown in Table 4, the presence of a hydroxyalkylidene
group on --R'-- and one or more polar groups (hydroxyalkyl,
hydroxyl or acetyl) on the aryl ring decreases the likelihood of
passage across the BBB. As illustrated by FIG. 1, CPS-179, CPS-190,
CPS-192 and CPS-195 produced cooling on the skin of the upper lip
with duration of action of more than 1 hr at concentrations of 0.5%
ointment. The ADME parameters for these chemicals (Table 4), and
the calculated log P value of less than 3.5 is favorable for
topical penetration into tissue targets. Protein binding is not a
significant factor affecting the distribution of these compounds.
Thus, CPS-179, CPS-190, CPS-192 and CPS-195 were deemed suitable as
candidates for development as antinociceptive agents. entry past
the blood-brain-barrier. TABLE-US-00004 TABLE 4 Hydroxyalkylidene
substituents on R' in structures reduces penetration of the
blood-brain-barrier. R--CO--N(R'')--R'--Y Formula 1 Substituents on
Y, Water Entry % protein code R' where Y = Phenyl log P solubility
into BBB bound CPS-177 --CH.sub.2--CH(OH)-- 4''-CH.sub.2OH 2.71
0.265 low 68 CPS-190* --CH.sub.2--CH(OH)-- 3'', 4''-OH 2.57 0.361
low 52 CPS-178 --CH.sub.2--CH(CH.sub.2OH)-- 3''-CH.sub.2OH,
4''-C(.dbd.O)--CH.sub.3 2.83 0.256 low 67 CPS-191*
--CH.sub.2--CH(OH)-- 3''-CH.sub.2--CH.sub.2OH,
4''-C(.dbd.O)--CH.sub.3 2.83 0.165 low 44 CPS-179
--CH.sub.2--CH(CH.sub.2OH)-- 4''-C(.dbd.O)--CH.sub.3 2.98 0.066 low
68 CPS-192 --CH.sub.2--CH(OH)-- 3''-OH 2.98 0.228 low 33 CPS-193*
--CH.sub.2--CH(OH)-- 3''-OCH.sub.3, 4''-C(.dbd.O)--CH.sub.3 3.05
0.074 low 35 CPS-l94* --CH.sub.2--CH(OH)-- 3''-OH, 4''-OCH.sub.3
3.06 0.161 low 50 CPS180 --CH.sub.2--CH.sub.2--CH.sub.2--
3''-CH.sub.2OH, 5''-CH.sub.2OH 3.26 0.270 low 70 CPS-l95*
--CH.sub.2--CH(OH)-- 3''-OH 3.29 0.317 low 32 CPS-183
--CH(CH.sub.2OH)-- none 3.41 0.070 high 72 CPS-185
--CH.sub.2--CH.sub.2-- 2''-CH.sub.2OH, 5''OH 3.55 0.252 low 68
CPS-186 --CH.sub.2--CH.sub.2--CH.sub.2-- 3''-CH.sub.2OH,
4''-C(.dbd.O)--CH.sub.3 3.57 0.073 low 69 CPS-l96*
--CH.sub.2--CH.sub.2-- 3'', 4''OH 3.76 0.051 high 48 CPS-187
--CH.sub.2--CH.sub.2--CH(OH)-- none 3.85 0.086 high 73 CPS-l97*
--CH.sub.2--CH.sub.2-- 3''-CH.sub.2--CH.sub.2OH 3.85 0.086 high 27
*R'' = --CH.sub.3 = asterisked compounds in the first column are
N-methylated. The parameters obtained in this Table were from a
commercial computer analysis program for ADMET prediction. BBB =
brain-brain-barrier, Water solubility = mol/L, logP = log
octanol/water partition coefficient. These parameters were obtained
using a commercial computer analysis program for ADMET
prediction.
[0065] In summary, I have found that N-acylation of direct and
indirect acting sympathomimetic drugs with a cooling pharmacophore
such as p-menthane carbonyl increases duration of drug action. It
was also found that introduction of a hydroxyalkylidene function
(e.g. hydroxymethylidene or hydroxyethylidene) into a molecular
pharmacophore of a cooling agent has the beneficial effect of
reducing the likelihood of this molecule crossing the
blood-brain-barrier. Other functional groups that enhance polarity
are hydroxyl and acetyl, but not alkoxy. Thus, the incorporation of
a hydroxyalkylidene group allows the drug to be administered in
hydrophilic medium for topical applications and increases the
versatility for clinical applications. Topical delivery to the
lining of the upper airways is of special interest. The insights
into the molecular parameters of pharmacokinetics are utilized for
the selection of ideal antinociceptive drug candidates.
[0066] It is to be understood that while the disclosure has been
described above in conjunction with preferred specific embodiments,
the description and examples are intended to illustrate and not to
limit.
* * * * *